Epileptic activity increases cerebral amino acid transport...
Transcript of Epileptic activity increases cerebral amino acid transport...
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Original Article
Epileptic activity increases cerebral amino acid transport assessed by [18F]-
fluoroethyl-L-tyrosine amino acid PET - a potential brain tumor mimic
Running Title
Epileptic activity and 18F-FET PET
Author Affiliations
Markus Hutterer,1,2,3,* Yvonne Ebner,3 Markus J. Riemenschneider,2,4 Antje Willuweit,5 Mark
McCoy,6 Barbara Egger,7 Michael Schröder,1 Christina Wendl,8 Dirk Hellwig,9 Jirka Grosse,9
Karin Menhart,9 Martin Proescholdt,2,10 Brita Fritsch,11 Horst Urbach,12 Guenther
Stockhammer,13 Ulrich Roelcke,14 Norbert Galldiks,5,15 Philipp T. Meyer,16 Karl-Josef
Langen,5,17 Peter Hau,1,2 and Eugen Trinka3
1Department of Neurology, University of Regensburg Medical School, Regensburg, Germany;
2Wilhelm Sander-Neurooncology Unit, University of Regensburg Medical School, Regensburg,
Germany; 3Department of Neurology and Centre for Cognitive Neuroscience, Christian-Doppler
Klinik, Paracelsus Medical University Salzburg, Salzburg, Austria; 4Department of
Neuropathology, University of Regensburg Medical School, Regensburg, Germany; 5Institute of
Neuroscience and Medicine, Forschungszentrum Jülich, Jülich, Germany; 6Department of
Radiology and Division of Neuroradiology, Christian-Doppler Klinik, Paracelsus Medical
University Salzburg, Salzburg, Austria; 7Department of Nuclear Medicine, Landeskrankenhaus
Salzburg, Paracelsus Medical University Salzburg, Salzburg, Austria; 8Department of Radiology
Journal of Nuclear Medicine, published on July 28, 2016 as doi:10.2967/jnumed.116.176610by on October 22, 2020. For personal use only. jnm.snmjournals.org Downloaded from
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and Division of Neuroradiology, University of Regensburg Medical School, Regensburg,
Germany; 9Department of Nuclear Medicine, University of Regensburg Medical School,
Regensburg, Germany; 10Department of Neurosurgery, University of Regensburg Medical
School, Regensburg, Germany; 11Department of Neurology, University Hospital Freiburg,
Freiburg, Germany; 12Department of Neuroradiology, University Hospital Freiburg, Freiburg,
Germany; 13Department of Neurology, Medical University Innsbruck, Innsbruck, Austria;
14Department of Neurology and Brain Tumor Center, Cantonal Hospital Aarau, Aarau,
Switzerland; 15Department of Neurology, University of Cologne, Cologne, Germany;
16Department of Nuclear Medicine, University Hospital Freiburg, Freiburg, Germany;
17Department of Nuclear Medicine, University of Aachen, Aachen, Germany
*Corresponding Author
Markus Hutterer, MD; Department of Neurology and Wilhelm-Sander NeuroOncology Unit,
University of Regensburg Medical School, Franz Josef Strauß-Allee 11, D-93053 Regensburg,
Germany; Phone: 0049/(0)941-941-0, Fax: 0049/(0)941-941-3055, Email:
Key Words
epileptic seizure, status epilepticus, 18F-FET PET, glioma, LAT1/2 expression
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Number of characters in the title: 146
Number of characters in the running head: 34
Number of words in abstract: 258
Numbers of words - main text: 3630
Numbers of words - all data: 6928
Number of tables: 2 (+ 1 supplemental Table 1)
Number of color figures: 4 (+ 1 supplemental Fig. 1)
Number of references: 39
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ABSTRACT
O-(2-[18F]-fluoroethyl)-L-tyrosine positron emission tomography (18F-FET PET) is a well-
established method increasingly used for diagnosis, treatment planning and monitoring in
gliomas. Epileptic activity, frequently occurring in glioma patients, can influence MRI findings.
Whether seizures also affect 18F-FET PET imaging is currently unknown. The aim of this
retrospective analysis was to investigate the brain amino acid metabolism during epileptic
seizures by 18F-FET PET and to elucidate the pathophysiological background.
Methods. Ten patients with eleven episodes of serial seizures or status epilepticus, who
underwent MRI and 18F-FET PET, were studied. The main diagnosis was glioma WHO grade II-
IV (n=8), two patients suffered from non-neoplastic diseases. Immunohistochemical assessment
of LAT1/LAT2/CD98 amino acid transporters was performed in seizure-affected cortex (n=2)
and compared with glioma tissues (n=3).
Results. All patients exhibited increased seizure-associated strict gyral 18F-FET uptake, which
was reversible in follow-up studies or negative shortly before and without any histological or
clinical signs of tumor recurrence. 18F-FET uptake corresponded to structural MRI changes,
compatible with cortical vasogenic and cytotoxic edema, partial contrast enhancement and
hyperperfusion. Patients with prolonged postictal symptoms lasting up to eight weeks displayed
intensive and widespread (≥ one lobe) cortical 18F-FET uptake. LAT1/LAT2/CD98 was strongly
expressed in neurons and endothelium of seizure-affected brains, and less in reactive
astrocytosis.
Conclusions. Seizure activity, in particular status epilepticus, increases cerebral amino acid
transport with a strict gyral 18F-FET uptake pattern. Such “periictal pseudoprogression”
represents a potential pitfall of 18F-FET PET and may mimic brain tumor. Our data also indicate
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a seizure-induced upregulation of neuronal, endothelial and less astroglial LAT1/LAT2/CD98
amino acid transporter expression.
INTRODUCTION
Positron emission tomography (PET) with the amino acid tracer O-(2-[18F]-fluoroethyl)-L-
tyrosine (18F-FET) is increasingly used as an adjunct to magnet resonance tomography (MRI) for
brain tumor diagnosis, treatment planning and monitoring (1,2). 18F-FET uptake is primarily
mediated by the system L amino acid transporter subtypes LAT1 and LAT2 (3,4). These
transporters are heterodimers consisting of a light (LAT1, LAT2) and a heavy chain (CD98) and
function as obligatory stereospecific exchanger (antiporter) of neutral amino acids (3,4).
LAT1/LAT2 are highly expressed in primary brain tumors. The highest levels have been
detected in glioma cells and tumor-associated endothelium (5). Consequently, 18F-FET PET has
a high specificity for gliomas mediated by a tracer uptake almost independent of blood-brain
barrier (BBB) dysfunction. 18F-FET uptake by non-neoplastic tissue is considered as a rare
phenomenon and has been reported for various inflammatory and vascular brain lesions (1,6-10).
Epileptic seizures are among the most common symptoms of primary brain tumors (11).
Focal symptoms after seizures usually disappear within 36 hours (12-14). Prolonged postictal
deficits, however, are often similar to symptoms that arise from progressive tumor growth. On
the other hand, an increase of seizure frequency may be an early sign of tumor progression
(11,15). Therefore, the differentiation of purely seizure-related postictal symptoms from tumor
progression is of paramount importance in the clinical management of brain tumor patients.
To complicate this matter, seizure activity, in particular status epilepticus, may result in
MRI changes difficult to differentiate from tumor progression (16). For 18F-FET PET it is still
unknown whether and to which extend seizures influence cerebral amino acid metabolism and
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18F-FET tracer uptake. Therefore, we retrospectively studied patients with serial epileptic
seizures or status epilepticus who underwent MRI and 18F-FET PET imaging with particular
focus on spatial distribution pattern and time course of 18F-FET uptake, and elucidated the
pathophysiological background by histopathological assessment of amino acid transporter
expression in specific cell types involved in epileptogenesis.
MATERIALS AND METHODS
Study design and data collection
We identified eight patients with gliomas WHO grade II-IV and two patients with non-
neoplastic diseases from three neurooncology centers (Salzburg, Austria; Regensburg and
Freiburg, Germany), who fulfilled the following inclusion criteria: (i) presentation with typical
clinical and/or electroencephalographic (EEG) signs of highly frequent seizures (several times
per day, serial seizures) or status epilepticus and (ii) multimodal imaging work-up consisting of
18F-FET PET and serial MRI scans.
According to the definitions of the International League Against Epilepsy types of
epileptic seizures were classified as simple partial seizure (SPS), complex partial seizure (CPS),
tonic-clonic seizure (TCS) and series of epileptic seizures (SES) (17). Status epilepticus (SE)
was defined as ≥5 minutes of convulsive seizures or ≥10 minutes of non-convulsive seizures
with impairment of consciousness confirmed by EEG criteria (18-20).
Clinical data, laboratory values, EEG, standard MRI, 18F-FET PET and histological records
of all patients were analyzed (Table 1). Besides MRI and 18F-FET PET during the course of
disease, MR perfusion-weighted imaging (PWI), 99mTc-Hexa-Methyl-Propylen-Aminooxim
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(99mTc-HMPAO) SPECT and 18F-2-Fluoro-2-Deoxy-D-Glucose (18F-FDG) PET scans at the time
of epileptic disorder were additionally evaluated if available.
The local ethics committee of the University of Regensburg approved this retrospective
study (number 14-101-0185) and the requirement to obtain informed consent was waived. The
study was conducted according to the standards of the Declaration of Helsinki in its recent
revised version of 2013.
Standard MR imaging
Standard MR imaging was routinely performed at the local departments of neuroradiology.
At the time of seizure disorder and afterwards in the course of disease, all patients received MRI
scans using 1.5 T or 3.0 T scanners with standard head coils before and after administration of a
gadolinium-based contrast agent. The routine MRI protocol included T1-weighted sequences
with and without contrast agent (T1w, T1wCE), T2 and FLAIR sequences, and MR diffusion-
weighted imaging (DWI) with calculation of the apparent diffusion coefficient (ADC). In five
patients, additional dynamic susceptibility contrast (DSC) PWI was available.
MR image analysis
For study evaluation, the cortical changes in standard MRI and, if available, DSC-PWI
were retrospectively reviewed by two independent investigators (C.W., M.H.). During this
analysis, contrast enhancement in T1wCE sequence (BBB permeability), T2/FLAIR sequences
(hyperintensity, vascular edema), DWI/ADC sequences (diffusion restriction, cytotoxic edema)
and DSC-PWI (hypo- or hyperperfusion) were graded visually on a three-point scale (no, weak
and strong).
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18F-FET PET imaging
18F-FET PET was routinely performed at the local departments of nuclear medicine
according to the German and Austrian guidelines for brain tumor imaging using labeled amino
acid analogues (21). All patients fasted for at least 6 hours before PET scanning. Prior to the
investigation, a low-dose computer tomography (CT) scan was performed for attenuation
correction. PET acquisition was started 20 minutes after intravenous injection of about 250 MBq
18F-FET with a scan duration of at least 20 minutes. The methodological differences between the
different neurooncology centers (PET scanner equipment, reconstruction methods, and
acquisition specifics) are summarized in supplemental Table 1. All 18F-FET PET scans were
conducted between March 2011 and June 2015.
18F-FET PET image analysis
18F-FET PET and MR images were co-registered using dedicated software (Vinci V4.40,
Max-Planck-Institute for Metabolism Research, Cologne, Germany). The results were reviewed
and, if necessary, adapted based on anatomical landmarks. The regions-of-interest (ROI) analysis
was based on the summed static 18F-FET PET data. The transaxial slice showing the highest
tracer accumulation in the brain lesion was chosen for ROI analysis. The tracer uptake in the
unaffected brain was determined by the largest possible ROI placed on the contralateral
hemisphere in an area of normal-appearing brain, including white and grey matter and excluding
basal ganglia, thalamus and ventricles. 18F-FET uptake was expressed as standardized uptake
values (SUV). The ROI of the suspicious lesion was determined using a three-dimensional
autocontouring process with a lesion-to-brain ratio (LBR) of ≥1.6 as described previously (22).
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Because of the reversibility of seizure-related cortical tracer uptake in follow-up studies and 18F-
FET PET shortly before seizure activity cortical LBRmax was <1.6. In these cases a circular ROI
with a diameter of 1.6 cm was centered exactly on the cortex of maximal 18F-FET uptake
observed during seizure activity. Mean and maximum LBRs (LBRmean, LBRmax) were calculated
by dividing SUVmean and SUVmax of the 18F-FET uptake by the mean SUV of the contralateral
unaffected hemisphere.
For study evaluation, the cortical changes in 18F-FET PET were assessed visually by two
independent investigators (J.G., M.H.). Cortical 18F-FET uptake extension was graded as “focal”
(extension ≤5 cm), “enlarged” (extension >5 cm, within one lobe), and “widespread” (more than
one lobe).
In one patient (case 3), a time-activity curve of SUVmean in the frontal epileptic brain lesion
was generated by measuring a spherical volume-of-interest of 2 ml centered on the maximal 18F-
FET brain lesion uptake and in a reference ROI of unaffected brain (as described above) using
the entire dynamic dataset.
Histological assessment and immunostaining
Histological specimen were available for study analysis from two patients of the study
cohort (Table 2): (i) patient case 3 with oligodendroglioma WHO grade II (no residual tumor)
and non-convulsive SE resulting in partial frontal lobe resection of seizure-affected cortex , and
(ii) patient case 7 with repeated CPS and TCS leading to first diagnosis of glioblastoma WHO
grade IV and resection of seizure-affected cortex and subcortical tumor. Seizure-affected cortex
was defined as cortical tissue with seizure-induced changes in MRI and 18F-FET PET and
without tumor cells in histopathological evaluation.
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For comparison, three tissue specimens of archival material with astrocytoma WHO grade
II , anaplastic astrocytoma WHO grade III and glioblastoma WHO grade IV were evaluated. All
specimens were assessed for the protein expression pattern of LAT1, LAT2 and CD98 using
formalin fixed and paraffin embedded (FFPE) tissues.
Immunohistochemical staining was performed according to standard protocols. Paraffin
sections were deparaffinized through an alcohol series and rehydrated. After antigen retrieval for
20 minutes (ethylene diamine tetra-acetic acid [EDTA] buffer, pH 8.5, Sigma-Aldrich) and a
blocking step, sections were incubated with the primary antibodies (LAT1/LAT2 for 45 minutes
at room temperature, CD98 overnight at 4 °C). The following primary antibodies were used:
rabbit-anti SLC7A5 (PA2187, Booster Immunoleader, 1:100), rabbit-anti SLC7A8 (NBP1-
70389, Novus Biologicals, 1:1000), rabbit-anti CD98 (bs-6659R, Bioss, 1:100).
Immunoreactivity was detected by the EnVisionTM Detection System (#K406511-2, Dako) and
3,3’-diaminobenzidine tetrahydrochloride (DAB, EnVision+, Dako) and afterwards
counterstained by hematoxylin. As positive control, FFPE tissue from placenta was used and
negative controls were run without the primary antibody. Neuropathological evaluation was
carried out by a board-certified neuropathologist (M.J.R.) blinded to clinical and imaging
findings. The immunostaining pattern of neurons, astrocytes, microglia, tumor and vascular
endothelial cells of tumor bulks and tumor infiltrative zones were analyzed separately.
RESULTS
Study population
In this multicenter study, ten patients with eleven episodes of SES/SE were identified
(eight patients with gliomas WHO grade II-IV; two patients with non-neoplastic diseases and
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final diagnoses of ischemic stroke and non-convulsive SE caused by septic encephalopathy;
Table 1). One patient presented with identical serial focal motor seizures and focal SE followed
by prolonged postictal hemiparesis in 2011 and 2014. Because combined MRI and 18F-FET PET
was available from both time points, this patient was examined twice (case 1 and 2). 18F-FET
PET was performed during or within 7 days after termination of the clinical and/or EEG signs of
seizure activity (Table 2). MRI and 18F-FET PET were also obtained out of an epileptic
episode. This was during the clinical follow-up after seizure initiation in 5 cases (range, +8 to
+12 weeks) and before seizure onset in 2 other cases (-4 and -10 weeks).
Structural MRI changes during seizure activity
During SES/SE and prolonged postictal symptoms we observed structural MRI changes
including cortical hyperintensity in T2/FLAIR sequences and diffusion-restriction with low ADC
values in DWI/ADC (9/11 cases; Table 2; Figs. 1-3; Supplemental Fig. 1), consistent with the
presence of cortical vasogenic and cytotoxic edema. In 3/11 cases, additional focal gyral contrast
enhancement in T1wCE was noted (Figs. 1 and 2). Cortical perfusion was increased in DSC-PWI
in 3/5 available cases with clinical and/or electrophysiological signs of SE or treatment-resistant
series of SPS (Figs. 1-3). Patients with high seizure frequency but without SE (2/11 cases) did
not exhibit any visible structural brain changes on standard MRI.
18F-FET uptake during seizure activity
Seven patients with SES/SE or prolonged postictal symptoms demonstrated increased 18F-
FET uptake strictly following the cortical ribbon of seizure-affected brain areas (cases 1-6, 10;
Table 2) corresponding to structural MRI changes. 18F-FET PET revealed increased LBRmax
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(range, 1.83 to 4.42; median ± standard deviation [SD], 3.95 ± 1.02) and LBRmean (range, 1.46 to
2.58; median ± SD, 2.27 ± 0.40). 18F-FET tracer uptake occurred in areas with and without
contrast enhancement in T1wCE (Figs. 1-3; Supplemental Fig. 1). In contrast, patients with TCS
followed by prolonged postictal hemiparesis (case 11; Supplemental Fig. 1D) or high frequent
seizures without SE (cases 7-9) exhibited lower LBRmax (range, 1.69 to 1.81; median ± SD, 1.77
± 0.05) and LBRmean (range, 1.42 to 1.57; median ± SD 1.49 ± 0.08) of more focally enhanced
cortical 18F-FET uptake (Supplemental Fig. 1).
In case 3, the time-activity curve of 18F-FET uptake in the frontal epileptic brain lesion was
calculated and compared to the unaffected contralateral hemisphere (Fig. 2D). The curve pattern
showed a continuously increasing 18F-FET uptake without clear identifiable peak uptake and
wash-out kinetics, comparable to that usually observed in low-grade gliomas.
18F-FET uptake and prolonged postictal symptoms
Four SES/SE patients showed an increased and widespread cortical 18F-FET uptake
spreading into two or three lobes, combined with cortical vasogenic and cytotoxic edema and
partial contrast enhancement in MRI (cases 1, 2, 5, 6). This observation was associated with
prolonged postictal symptoms lasting 1 to 6 weeks (Table 2).
In contrast, case 4 suffered from clinical stable anaplastic astrocytoma WHO grade III
without residual tumor over years and presented with a TCS followed by severe postictal
symptoms over 8 weeks (Fig. 3). This condition was associated with distinctly increased cortical
18F-FET uptake over three lobes of the left hemisphere with fronto-temporal accentuation
(LBRmax 3.95 and LBRmean 2.08) and slight cortical vascular and cytotoxic edema without
contrast enhancement in MRI. Importantly, there was no evidence of status epilepticus in EEG
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monitoring, 18F-FDG PET (regional hypometabolism) and 99mTc-HMPAO (regional
hypoperfusion; not shown in detail), indicating prolonged increased cerebral amino acid
metabolism in the postictal period.
Reversibility of metabolic and structural cortical changes
Follow-up MRI and 18F-FET PET scans from five patients were available after seizures
termination (range, 2 to 12 weeks). Despite antiepileptic treatment, patients with widespread and
extensive cortical 18F-FET uptake showed only a slow recovery of structural and metabolic
cortical changes within 4 to 12 weeks (Table 2; Fig. 1D; Figs. 3B-C). The figure 4A-C shows the
time course of 18F-FET uptake decrease. 18F-FET PET scans were performed 4 days (LBRmax
3.95, LBRmean 2.08), 11 days (LBRmax 2.34, LBRmean 1.45) and 12 weeks (no tracer uptake) after
seizure onset.
Histopathological evaluation and immunostaining
Since the results of MRI and 18F-FET PET findings suggested tumor recurrence or
progression, three patients underwent stereotactic biopsy or microsurgical resection of the
putative lesions (cases 1, 3, 6; Table 2). In those cases, standard neuropathological evaluation of
seizure-affected brain yielded cortical brain edema with reactive astrocytosis and microglia
activation without any evidence of tumor cells.
Based on the known transport mechanisms of 18F-FET, additional immunohistochemical
analysis of LAT1, LAT2 and CD98 protein expression was performed using FFPE tissue
specimens derived from partial frontal lobe resection of seizure-affected brain tissue in MRI and
18F-FET PET (case 3; Fig. 2 and Figs. 4A-B) and tumor resection of a newly diagnosed
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glioblastoma WHO grade IV including histological tumor-free cortex and subcortical tumor
tissue (case 7). For comparison, three tissue samples from archival material with astrocytoma
WHO grade II, anaplastic astrocytoma WHO grade III and glioblastoma WHO grade IV were
additionally evaluated (Figs. 4C-F).
In seizure-affected cortex, LAT1/LAT2/CD98 amino acid transporter showed a strong and
extended expression in neurons and brain endothelium (Figs. 4A-B), and was also detected in
reactive astrocytes, especially when located adjacent to brain capillaries (Fig. 4B). Overall,
LAT1/LAT2/CD98 staining in neurons and vascular endothelial cells was much more frequently
observed than in reactive astrocytosis. Within the glioma infiltration zone, cortical neurons also
revealed a pronounced expression of LAT1/LAT2/CD98, in particular when neurons and glioma
cells interacted directly (“tumor cells as satellites of neurons”, Fig. 4C). Additionally,
interspersed LAT1/LAT2/CD98 positive reactive astrocytes were observed (Fig. 4D). As
expected, glioma and tumor-associated endothelial cells strongly expressed LAT1/LAT2/CD98
(Figs. 4E-F).
DISCUSSION
For the first time, we report a substantial increase of cortical amino acid transport assessed
by 18F-FET PET during and after serial seizures or status epilepticus in patients with gliomas and
non-neoplastic brain lesions. Elevated 18F-FET tracer uptake appears to be associated with
cortical vasogenic and cytotoxic edema, hyperperfusion and contrast enhancement in MRI. 18F-
FET uptake was clearly not caused by tumor progression or relapse in the subgroup of glioma
patients, as proven by multimodal long-term follow-up MR/PET imaging and histological
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confirmation in three patients. Therefore, our observation represents a so far unknown limitation
of 18F-FET PET in brain tumor diagnosis resembling “periictal pseudoprogression”.
18F-FET uptake values in SES/SE patients were similar to those observed in high-grade
gliomas (LBRmax median ± SD, SES/SE vs. HGG, 3.95 ± 1.02 vs. 2.04 ± 0.72) (1). In contrast,
patients with frequent seizures but without SES/SE presented with lower and more focally
pronounced cortical 18F-FET uptake, comparable with values seen in low-grade gliomas (LBRmax
median ± SD, seizures vs. LGG, 1.77 ± 0.05 vs. 1.52 ± 0.70) (1). In addition, the time-activity
curve pattern of 18F-FET uptake corresponded to that described for low-grade gliomas (23).
Based on these results, it appears that 18F-FET tracer uptake values, and possibly dynamic 18F-
FET PET imaging, are not capable of distinguishing between seizure-induced alterations and
tumor progression. In contrast, typical findings for seizure-induced 18F-FET tracer uptake were
the strict gyral uptake pattern and the reversibility in follow-up-studies. Although
methodological differences between the neurooncology centers exist (Supplemental Table 1),
quantification of tracer uptake should in principle lead to similar results. In any case, it can be
assumed that the methodological differences are less relevant for intra-individual courses.
Structural changes of the brain cortex in MRI are the most stereotypic imaging features
suggesting seizure activity or status epilepticus (16). On this account, the combination of a strict
gyral, and mostly extended, 18F-FET uptake associated with cortical MRI changes and high
seizure activity, status epilepticus, or unusually prolonged postictal symptoms, should raise the
suspicion of “periictal pseudoprogression”. In order to avoid overtreatment, this phenomenon
must be considered in the interpretation of 18F-FET PET images and clinical decision making,
especially in patients suffering from cerebral glioma and symptomatic epilepsy.
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In general, transient postictal deficits are reversible within 36 hours (12-14). In our study
population, however, prolonged postictal symptoms were observed for up to 8 weeks after
seizure termination and were associated with structural and metabolic cortical changes of more
than one lobe in MRI and 18F-FET PET. In all patients with follow-up investigations, increased
gyral 18F-FET uptake, cortical edema, contrast enhancement and hyperperfusion normalized in
parallel with clinical symptoms and EEG findings. Therefore, if clinically justified, a close
clinical, MRI and 18F-FET PET follow-up for at least 8 weeks should be considered in these
patients before therapeutic decisions, in particular invasive procedures, are undertaken.
Our findings also provide new insights into the pathophysiological changes in seizure-
associated cortical amino acid metabolism. Previous studies have shown that 18F-FET does not
participate in specific metabolic pathways and is transported predominantly via the system L
amino acid transporters LAT1 and LAT2 (3,4). In normal cerebral cortex, LAT1 protein is only
moderately expressed and LAT2 protein is absent (24). In contrast, immunohistochemical
analysis of tissue specimen derived from seizure-affected cortex revealed a strong expression of
LAT1/LAT2/CD98 in neurons and brain endothelium, indicating a seizure-induced upregulation
of LAT1/LAT2 transporter mediating cortical 18F-FET tracer uptake.
Interestingly, also neurons in the infiltration zone of glial tumors strongly expressed
LAT1/LAT2/CD98, in particular when directly interacting with tumor cells as “satellites” (Fig.
4C). This observation supports the hypothesis of a link between LAT1/LAT2/CD98 expression
and epileptogenesis, since in glial brain tumors epileptogenic activity arises in the cortex
adjacent to the tumor, while the tumor itself is considered electrically inert with regard to seizure
initiation (25). Structural and metabolic changes in the peritumoral tissue may lead to cortical
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cell alterations with imbalance between excitatory and inhibitory neurotransmitter, especially
high intra- and peritumoral glutamate levels (25-27).
Reactive astrocytosis has been shown to be associated with increased 18F-FET uptake in
various non-neoplastic brain lesions (e.g., inflammatory and demyelinating lesions, brain
ischemia and hemorrhage, brain abscesses and radiation necrosis), representing another potential
“pitfalls” in 18F-FET PET (1,6-10). In the presented group of patients, however, there were no
clinical or radiological signs that would have been consistent with one of these differential
diagnoses. Furthermore, the presented lesions showed a strict gyral pattern, which is untypical
for the lesions mentioned above and suggests a connection with an epileptogenic genesis. This
notion is further supported by the fact that in specimen of seizure-affected cortex
LAT1/LAT2/CD98 was stronger expressed in neurons and brain endothelium than in reactive
astrocytes, indicating a predominant neuronal 18F-FET uptake during seizure activity.
Other aspects that need to be discussed concerns the relationship of seizure-mediated
increased 18F-FET uptake, regional blood flow and blood-brain-barrier disruption. Numerous
PET and SPECT studies using various tracers have shown that the cerebral blood flow is
increased in the ictal and decreased in the interictal state (28). In the present report, enhanced
cortical 18F-FET uptake was observed in brain areas with increased (Figs. 1-3) and decreased
regional perfusion as well as increased (Supplemental Fig. 1) and decreased (Fig. 3) glucose
metabolism. Similarly, previous studies have shown high 18F-FET uptake in gliomas with low
cerebral blood flow or blood volume (29,30). Therefore, it is unlikely that increased 18F-FET
uptake during seizure activity is caused by hyperperfusion to a major extent.
Along with gyral hyperperfusion most SES/SE patients developed a mixture of vasogenic
and cytotoxic edema, and partly contrast enhancement in MRI, indicating enhanced permeability
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and/or disruption of the BBB. BBB dysfunction is one of the earliest pathophysiological features
of status epilepticus mediated by several mechanisms, including glutamate receptor activation of
endothelial cells, rapidly activated brain inflammation, and seizure-associated angiogenesis
(31,32).
Although a correlation between 18F-FET uptake and contrast enhancement in brain tumors
has been reported (1), there are many examples of brain lesions with BBB disruption and
contrast enhancement (e.g. radionecrosis, abscesses) that are clearly negative on 18F-FET PET.
This observation excludes that 18F-FET uptake is significantly influenced by BBB disruption.
Therefore, it is most likely that the observed phenomenon of increased 18F-FET uptake in
epileptogenic brain areas is due to a process which mediates an upregulation of
LAT1/LAT2/CD98 expression in neurons and the brain endothelium.
Enhanced amino acid uptake during seizure activity has also been discussed in a few case
reports using 11C-methionine (11C-MET) (33-35), which is also transported via LAT1/LAT2
(36). Moreover, increased amino acid uptake in epileptic foci was reported for PET using α-
[11C]methyl-L-tryptophan (11C-AMT) (37,38), which measures the serotonin synthesis rate. It
was speculated that its increased uptake in epileptogenic tubers reflects changes in the
kynurenine pathway. Since L-tryptophan is also a substrate of LAT1/LAT2 (39), it is tempting to
hypothesis that increased 11C-AMT uptake in epileptogenic foci has also been influenced by
increased LAT1/LAT2 transport as observed in the present study for 18F-FET.
CONCLUSION
Seizure-induced increase of cerebral amino acid transport seems to be primarily mediated
by neuronal, endothelial and to a lesser extent astroglial LAT1/LAT2/CD98 expression. A strict
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gyral 18F-FET uptake in combination with cortical MRI changes, high seizure activity and
unusually prolonged postictal focal symptoms, should raise the suspicion of “periictal
pseudoprogression”. In order to avoid overtreatment, this phenomenon has to be taken into
account in the interpretation of 18F-FET PET images and a close clinical and MRI/18F-FET PET
reevaluation for at least 8 weeks should be considered.
ACKNOWLEDGMENTS
We thank Nicole Niemietz and Maria Hirblinger for excellent technical assistance.
POTENTIAL CONFLICTS OF INTEREST
The authors have no conflicts of interest related to this work and confirm the originality of
this study. All authors have seen and agree with the contents of the manuscript. The Journal of
Nuclear Medicine requirements for authorship have been met. Parts of the study were presented
at the 2014 Scientific Meeting of the Society for Neurooncology (SNO) as poster.
FUNDING INFORMATION
No funding.
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Abbreviations
11C-AMT α-[11C]methyl-L-tryptophan
11C-MET [11C]-methionine
18F-FDG [18F]-2-Fluoro-2-Deoxy-D-Glucose
18F-FET O-(2-[18F]-fluorethyl)-L-tyrosine
99mTc-HMPAO [99mTc]-Hexa-Methyl-Propylen-Aminooxim
ADC apparent diffusion coefficient
CD98 4F2hc/CD98,heavysubunitofLATtransporter
CPS complex partial seizure
DWI diffusion-weighted imaging
FFPE formalin fixed and paraffin embedded tissue
FLAIR fluid attenuated inversion recovery
LAT1/2 L-type amino acid transporter, light subunit of LAT transporter
LBR lesion-to-brain ratio
PWI perfusion-weighted imaging
SD standard deviation
SE status epilepticus
SES series of epileptic seizures
SPS simple partial seizure
SUV standardized uptake values
T1w T1-weighted sequence
T1wCE contrast enhanced T1-weighted sequence
TCS tonic-clonic seizure
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TTP time-to-peak
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Figure 1
Figure 1. Structural and metabolic changes in MRI and 18F-FET PET in focal status
epilepticus. Case 1 represents a 64-year old female with clinically stable right frontal anaplastic
astrocytoma WHO III without residual tumor. In 2011, she developed a series of treatment-
refractory motor SPS and a focal SE of the left arm and leg, followed by a severe and prolonged
postictal left hemiparesis for 4 weeks. (A-C) MRI and 18F-FET PET was performed
simultaneously with motor SPS and revealed a distinct increased and extended cortical 18F-FET
uptake right temporo-parieto-occiptal (LBRmax 4.18, LBRmean 2.58) associated with cortical
vasogenic (T2/FLAIR hyperintensity) and cytotoxic (diffusion-restriction in DWI + low ADC
values) edema, contrast enhancement (T1wCE, BBB leakage) and hyperperfusion (PWI-PBP,
baseline at peak map). 18F-FET uptake was observed independently from BBB disruption in
cortex with (*) and without (+) contrast enhancement in T1wCE. (D) Nine weeks after seizure
onset and antiepileptic treatment, structural and metabolic MRI and 18F-FET PET signal
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alterations completely resolved, except for slight cortical atrophy in T1 and T2/FLAIR. In 2014,
the same patient again developed a treatment-resistant series of motoric SPS with prolonged
postictal hemiparesis for 4 weeks with similar morphological and metabolic changes in MRI/18F-
FET PET (LBRmax 4.02, LBRmean 2.50) (not shown).
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Figure 2
Figure 2. Widespread 18F-FET uptake, vasogenic and cytotoxic edema, contrast
enhancement and hyperperfusion with strict gyral pattern during non-convulsive status
epilepticus. Case 3 demonstrates a 66-year old female with clinically stable right frontal
oligodendroglioma WHO II without residual tumor. In 2014, the patient presented with repeated
CPS followed by treatment-resistant non-convulsive SE. (A) 18F-FET PET revealed a distinct
elevated cortical 18F-FET uptake of the right hemisphere with frontal and parietal accentuation
(LBRmax 4.42, LBRmean 2.45), corresponding to cortical contrast enhancement in T1wCE, marked
gyral vasogenic (T2/FLAIR, cortical swelling) and cytotoxic (DWI/ADC) edema and (B) cortical
hyperperfusion in DSC-PWI (CBF cerebral blood flow; CBV, cerebral blood volume; MTT,
mean transit time; TTP, time to peak). (C) Clinical deterioration in combination with MRI and
18F-FET PET imaging was interpreted as tumor recurrence. Therefore, the patient underwent
subtotal frontal lobe resection without any histological evidence of tumor progression. (D)
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Additional 18F-FET kinetic analysis of the right frontal lesion and normal contralateral brain
demonstrated a SUVmean time-activity-course curve pattern with continuously increasing 18F-FET
uptake without wash-out.
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Figure 3
Figure 3. Cortical amino cid metabolism in 18F-FET PET in the course of a prolonged
postictal episode. Case 4 demonstrates a 44-year old male with clinically stable anaplastic
astrocytoma WHO III without any residual tumor over years who presented with TCS followed
by severe and prolonged postictal symptoms (global aphasia, right-sided hemiplegia and
hemineglect) over 8 weeks. (A) MRI (day 1) and 18F-FET PET (day 4) showed a distinct
increased and extended cortical 18F-FET uptake of the left brain hemisphere (LBRmax 3.95,
LBRmean 2.08) with frontal and temporal accentuation, corresponding to slight cortical vasogenic
and cytotoxic edema (T2/FLAIR, DWI/ADC) without contrast enhancement (T1wCE). EEG
monitoring, 18F-FDG PET (glucose hypometabolism, red arrows) and 99mTc-HMPAO SPECT
(hypoperfusion, only written report available), however, revealed no evidence of status
epilepticus. (B) 18F-FET PET 11 days after symptom onset and 7 days after first 18F-FET PET a
slight regression of cortical 18F-FET uptake (LBRmax 2.34, LBRmean 1.45) was observed. (C) The
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patient slowly recovered within 8 weeks after seizure onset. 18F-FET PET and MRI 12 weeks
after symptom onset demonstrated complete recovery of cortical 18F-FET uptake and brain
edema, only residual cortical atrophy in T1 and T2/FLAIR sequences remained.
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Figure 4
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Figure 4. LAT1, LAT2 and CD98 protein expression pattern in seizure-affected and glioma
tissue. LAT1, LAT2 and CD98 protein expression pattern in seizure-affected and tumor tissue.
(A) LAT1, LAT2 and CD98 showed strong and widespread expression in neurons of seizure-
affected cortex obtained from a patient with non-convulsive status epilepticus and subtotal
frontal lobe resection (case 3; Fig. 2; blue arrow = neuron; red arrow = vessel). (B) LAT1, LAT2
and CD98 were also detected in brain endothelial cells and reactive astrocytes (astrocyte-
endothelium interaction as part of the blood-brain barrier; red arrow = vessel, black arrow =
reactive astrocyte). Overall, LAT1, LAT2 and CD98 expression from neurons was more frequent
than that from reactive astrocytes as reactive astrocytosis was only focally represented. (C)
Within the infiltration zone of an astrocytoma WHO grade II cortical neurons revealed a
pronounced staining of LAT1/LAT2/CD98, in particular when glioma cells directly interact with
neurons (“tumor cells as satellites of neurons”; blue arrow = neuron, open black arrow =
satellitosis by tumor cells). (D) In addition, sporadic LAT1/LAT2/CD98 positive reactive
astrocytes were observed within the tumor infiltration zone. In comparison, tumor cells and
tumor endothelium of (E) anaplastic astrocytoma WHO grade III and (F) glioblastoma WHO
grade IV were also strongly positive for LAT1, LAT2 and CD98 expression.
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Case Center Age (y) Sex Diagnosis Tumor localization Treatment Disease status Seizure disorder before
1+2* F 64 f AA (1989) right frontal SU, RA, CT 1989 SD, no residual tumor yes (motor SPS, TCS)
3 R 66 f O (1985) right frontal SU, RA, PCV 1985 SD, no residual tumor yes (motor SPS)
4 S 44 m A (1991) OA (1996) AOA (1997)
left fronto-temporal SU 1991, 1996, 1997 RA/BCNU 1997
SD, no residual tumor yes (TCS)
5 R 54 m A (2014) left fronto-parietal SU, TMZ 2014 PD of residual tumor yes (motor SPS)
6 S 68 f O (2004) AO (2011)
right frontal SU 2004 SU, RA/TMZ 05/2011 CCNU 11/2011
SD, residual tumor yes (motor SPS, TCS)
7 R 51 m GBM (2013) right frontal SU 2013 ID of GBM yes (CPS, TCS)
8 R 29 f A (2012) sGBM (2015)
right fronto-parietal SU 2012, TMZ 2012-2013 SU + RA/TMZ 2015
PD of residual tumor yes (motor/sensory SPS, TCS)
9 R 45 m AO (2012) right fronto-temporal SU, RA/TMZ 2012 PC 2014 BEV/CCNU 2014-2015
SD, residual tumor no
10 R 76 f Non-convulsive SE caused by septic encephalopathy (06/2013)
Anticonvulsive treatment no recovery yes (non-convulsive SE 04/2013)
11 S 66 f Embolic cerebral ischemia (2011) Anticonvulsive treatment seizure free after 1 day
no
Table 1. Patient characteristics at the time of seizure diagnosis
Abbreviations: (m) male, (f) female; (F) Freiburg - Germany, (R) Regensburg – Germany, (S) Salzburg – Austria; (ID) initial
diagnosis; (A) astrocytoma WHO II, (OA) oligoastrocytoma WHO II, (O) oligodendroglioma WHO II, (AA) anaplastic astrocytoma
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WHO III, (AO) anaplastic oligodendroglioma WHO III, (AOA) anaplastic oligoastrocytoma WHO III; (GBM) glioblastoma WHO IV
(s, secondary); (SU) surgery, (RA) radiotherapy, (TMZ) temozolomide, (BCNU) carmustine, (CCNU) lomustine, (PC) procarbacine +
CCNU, (BEV) bevacizumab; (SD) stable disease, (PD) progressive disease
(*) The patient presented with the same clinical symptoms and EEG findings according to status epilepticus in 2011 and 2014. At both
time points combined MRI and 18F-FET PET imaging was available.
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EEG Cortical MRI Changes* 18F-FET PET* Disease Course
EE
G F
indi
ngs
Hem
isph
ere+
Lob
e(s)
+
T1w
CE
†
T2/
FL
AIR
†
DW
I/A
DC
†
PW
I†
LB
Rm
ax
LB
Rm
ean
ML
V
Upt
ake
Ext
ensi
on‡
Epi
-PE
T D
urat
ion§
Bio
psy/
Sur
gery
¶
Sym
ptom
Dur
atio
n║
18F
-FE
T P
ET
P
re-i
nves
tiga
tion
(-)
F
ollo
w u
p (+
)
18F
-FE
T R
ever
sibi
lity
LB
Rm
ax
LB
Rm
ean
ML
V
Case Diagnosis
1 Treatment-resistant serial motor SPS and focal SE, prolonged postictal hemiparesis (2011)**
SA R P, T, O
+ ++ ++ ++ 4.18 2.58 236 +++ sim BIEPI 4w +9w yes 1.22 1.09 0
2 Treatment-resistant serial motor SPS and focal SE, prolonged postictal hemiparesis (2014)**
SA R P, T, O
+ ++ ++ ++ 4.02 2.50 271 +++ sim - 4w +12w yes 1.24 1.11 0
3 Serial CPS followed by non-convulsive SE, prolonged postictal symptoms
SE R F, P, T
+ ++ ++ ++ 4.42 2.45 212 +++ 6d SUEPI na na -
4
TCS followed by prolonged postictal symptoms
SA L F, P, T
- ++ ++ na 3.95 2.08 203 +++ 4d - 8w +11d +12w
yes yes
2.34 1.16
1.45 1.07
83 0
10 Serial CPS followed by non-convulsive SE (septic encephalopathy)
SE L P, T, O
- ++ ++ na 2.47 1.68 76 +++ 5d - nr na -
5 Daily (5-10) motor SPS followed by focal motor SE
SE L F - ++ ++ ++ 2.63 1.71 26 ++ 7d - 2w na -
6 Repeated motor SPS, secondarily TCS followed by focal acoustic SE
ED, SA
R F, P - + ++ na 1.83 1.46 19 ++ 5d SUEPI 1w -4w yes 1.18 1.09 0
11 TCS with postictal hemiparesis ED, SA
R F - + ++ na 1.81 1.42 23 + 3d - 1d na -
7 Repeated CPS and one ED, R F - + + na 1.78 1.54 8 + 5d SUTU 1d +8w yes 1.20 1.07 0
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secondarily TCS SA
8 Daily (1-3) sensory SPS na R F - - - na 1.75 1.57 16 + sim SUTU - -10w yes 1.23 1.10 0
9 Daily (1-2) CPS SA R F - - - - 1.69 1.43 12 + sim - - +10w yes 1.19 1.12 0
Table 2. Overview on seizure activity, EEG findings, MRI and 18F-FET PET imaging and disease course of the study
population
Abbreviations: (SE) status epilepticus, (SA) slow activity, (ED) epileptic discharges; (nr) not recovered; (na) not assessed or available,
(LBR) lesion-to-brain ratio, (MLV) metabolic lesion volume [ml]
Footnotes: (*) Evaluation of structural and metabolic cortical changes in MRI and 18F-FET PET, (+) Tumor localization [(L) left, (R)
right and (F) frontal, (P) parietal, (T) temporal, (O) occipital]; (†) Visual assessment of cortical MRI changes [(-) no, (+) weak, (++)
strong]; (‡) Visual assessment of cortical 18F-FET uptake extension [(+) focal (one lobe and ≤ 5 cm), (++) enlarged (one lobe and > 5
cm), (+++) widespread (more than one lobe)]; (§) Time period between seizure onset or last EEG finding and 18F-FET PET in (d) days
or (sim) simultaneous; (¶) (SUTU) surgery due to tumor progression, (SUEPI/BIEPI) surgery/biopsy due to false positive tumor diagnosis
in MRI/PET, (-) no surgery/biopsy; (║) Time period between seizure onset and complete recovery or adequate seizure control [(d)
days, (w) weeks]; (**) The patient presented with identical clinical symptoms and EEG findings in 2011 and 2014 and was evaluated
twice;
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Doi: 10.2967/jnumed.116.176610Published online: July 28, 2016.J Nucl Med. Günther Stockhammer, Ulrich Roelcke, Norbert Galldiks, Philipp Meyer, Karl-Josef Langen, Peter Hau and Eugen TrinkaSchröder, Christina Wendl, Dirk Hellwig, Jirka Grosse, Karin Menhart, Martin Proescholdt, Brita Fritsch, Horst Urbach, Markus Hutterer, Yvonne Ebner, Markus J Riemenschneider, Antje Willuweit, Mark McCoy, Barbara Egger, Michael F]-fluoroethyl-L-tyrosine amino acid PET - a potential brain tumor mimic
18Epileptic activity increases cerebral amino acid transport assessed by [
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